Homeostatic organ preservation system

ABSTRACT

A homeostatic organ preservation system includes structure for defining a chamber for holding a donor organ, and a pump for providing a perfusion solution to the organ. A first conduit is coupled to the pump and is adapted to be coupled to the organ. The first conduit provides perfusion solution from the pump to the organ. A second conduit is coupled to the pump and to the organ chamber. The second conduit returns perfusion solution from the organ chamber to the pump. A pressure sensor is coupled to the first conduit to sense the pressure of the perfusion solution in the first conduit. The pressure sensor provides an output signal which is indicative of the vascular resistance of the organ. A pump control circuit is also included. The pump control circuit is responsive to the output signal of the pressure sensor to raise and lower the pump pulse rate respectively in response to a decrease and increase in the organ vascular resistance. A method of perfusing the donor organ, in which the organ is placed in the chamber and connected to a conduit which, in turn, is connected to a pump, includes the steps of monitoring the pressure of the perfusion solution in the conduit, and adjusting the pump pulse rate in accordance with the pressure of the perfusion solution. The pulse rate of the pump is decreased if the resistance of the perfused organ increases, and will be increased if the resistance of the perfused organ decreases.

CROSS REFERENCE TO RELATED APPLICATIONS

This application is a continuation-in-part of co-pending priorapplication Ser. No. 07/380,870, filed Jul. 17, 1989, now abandoned.

BACKGROUND OF THE INVENTION

1. Field of the Invention

This invention relates to a homeostatic organ preservation system, andmore particularly relates to a method and apparatus for perfusing anorgan or the whole body of a non-heart beating cadaver. Even morespecifically, the invention relates to a pump for use in an organpreservation system.

The science of organ preservation has been rapidly increasing inimportance over recent years because of the increase in organtransplantation as a medical procedure. Basically, in organpreservation, an organ, such as a kidney, pancreas, liver, lung orheart, is removed from a donor and maintained in a viable condition byartificial means. This is done to maintain the organ until the recipientis selected and prepared to receive it.

Current procurement technology allows the removal of organs frombrain-dead trauma victims, that is, heart-beating donors who areotherwise in good physiological state. Another source of transplantableorgans is victims of motor vehicle accidents who succumb to theirinjuries in the emergency room or in the intensive care unit, in otherwords, non-heart beating donors. However, utilization of organs removedfrom these donor sources is limited, basically because of the timerequired to obtain consent from the families of the potential donorsprior to retrieval of such organs and the need to secure an operatingroom. Accordingly, in situ flush and cooling of organs would beadvantageous in such situations.

Irrespective of the source from which the donor organs are retrieved, itis important to cool the targeted organ rapidly to minimize thedeleterious effects of warm ischemia to the organ's microvasculature.Usually, a rapid flush of the organ's microvasculature, which results inthe rapid cooling of the organ, for example, to less than 15° C. in thecase of a kidney, and removal of red blood cells from themicrocirculation should be performed as soon as possible, for example,within about one half-hour in the case of a kidney, following cessationof blood flow through the organ. This rapid cooling of the organ shouldbe followed by the maintenance of cold temperature for a given period oftime while the recipient is selected and prepared to receive the organ.

2. Description of the Prior Art

Generally, current organ preservation systems incorporate a pump whichis designed to deliver cold perfusate at a constant flow. Duringperfusion, as the organ's vascular resistance increases, the perfusionpressure increases to maintain flow. Accordingly, one of the problemswith current organ preservation pumps is that they tend to damage thedelicate microvasculature of the organ which, in turn, causes themicrovasculature resistance to further increase. In response to thisfurther increase in resistance, the conventional pump further increasespressure, resulting in greater tissue injury.

A typical organ preservation pump is Model No. MOX-100TMA, manufacturedby Waters Instruments, Inc. of Rochester, Minn. The Waters Instrumentspump, in many ways, simulates the action of the heart in providing acold perfusion solution to a donor organ previously removed and beingmaintained in a viable state prior to transplantation. The pumpincorporates a lever arm which compresses an elongated resilient tube.The tube is coupled to the donor organ. The frequency of compression ofthe lever arm is manually adjustable, but usually is set at a relativelyhigh pulse rate, that is, about 60 beats per minute. This action causesperfusate to flow into the donor organ. In the above described WatersInstruments Company device, the donor organ is maintained in a containerconnected to the machine. It is the perfusion solution which cools theorgan. Thus, if perfusion ceases, the organ will warm up and damage tothe organ may occur.

There are also non-pulsating types of organ perfusion apparatuses. Suchapparatuses provide a preset "trickle" flow of perfusate to the isolatedorgan. Generally, these devices do not have any feedback control of theperfusate flow rate or pressure. Without such feedback control, there isno way of determining whether the organ is being sufficiently perfused.A hypothermic isolated organ does not have the neurological connectionto protect itself by constricting its vasculature under high pressureconditions, or by dilating to open its capillaries to allow more flow.Thus, without feedback control, these apparatuses may be providingperfusate to the organ at inadequate or undesirably high volumes andpressures.

Besides the problem of forcing a given volume of perfusion solution intothe organ under excessive pressure, which may result in damage to theorgan's microvasculature, conventional organ preservation systemsgenerally do not allow for the low pulse rates required duringhypothermic organ perfusion. Furthermore, current machines are limitedto a few hours of battery power and need frequent replacement of the icecontainer.

In addition, currently available organ preservation machines can weighmore than 25 kilograms and are relatively large. Such machines also maycost upwardly of $15,000 or more and $500 per disposable cassette, ifsuch is provided.

OBJECTS AND SUMMARY OF THE INVENTION

It is an object of the present invention to provide a homeostatic organpreservation system and a method and apparatus for perfusing a targetedorgan which minimizes damage to the organ's microvasculature.

It is another object of the present invention to provide an organpreservation system which incorporates a pump which is adapted tooperate at low pulse rates, which are preferable during hypothermicorgan perfusion.

It is yet another object of the present invention to provide an organperfusion apparatus and method, which will automatically respond tochanges in vasculature resistance to prevent tissue damage to the organ.

It is a further object of the present invention to provide an apparatusand method for perfusing a donor organ, which apparatus allows foradjustments in flow, pressure, pulse rate and the differential ofpressure over time over a wider range than conventional perfusionmachines.

It is yet a further object of the present invention to provide an organpreservation system which incorporates a pump which can be used toperfuse organs in situ in the course of whole body perfusion done forremoval of organs for transplantation or as a means to flush and reduceorgan temperature in situ in a semi-invasive fashion until consent fororgan donation is obtained.

In accordance with one form of the present invention, a homeostaticorgan preservation system includes structure defining a chamber forholding a donor organ, and a pump for providing a perfusion solution tothe organ. A first conduit is coupled to the pump and is adapted to becoupled to the organ. The first conduit provides perfusion solution fromthe pump to the organ. A second conduit is also coupled to the pump andto the structure defining the organ chamber. The second conduit isadapted to return perfusion solution from the organ chamber to the pump.The pump is operable to provide perfusion solution to the organ at apredetermined pump pulse pressure and pump stroke volume. Accordingly,the pump, first and second conduits and the organ chamber may be viewedas defining a circuit for recirculating perfusion solution between theorgan and the pump.

The homeostatic organ preservation system further includes a pressuresensor which is coupled to the first conduit. The pressure sensor sensesthe pressure of the perfusion solution in the first conduit and providedto the organ. The pressure sensor provides an output signal which isindicative of the vascular resistance of the organ.

A pump control circuit is also provided. As its name implies, the pumpcontrol circuit controls the pump and is responsive to the output signalof the pressure sensor to raise and lower the pump pulse raterespectively in response to a decrease and increase in the organvascular resistance.

In a more preferred form of the invention, the structure defining theorgan chamber, pump and first and second conduits may all be housed inan outer insulated container, which container may be filled with crushedice or the like to maintain the organ and the perfusate at a constanttemperature whether the pump is on or off.

In accordance with one form of the method of perfusing a donor organ, anorgan is placed in a chamber and connected to a first conduit which, inturn, is connected to a pump. The organ chamber is further connected toa second conduit which is also connected to the pump. The pump providesa perfusion solution to the organ through the first conduit, and thesolution is returned to the pump via the second conduit.

The method further includes the step of monitoring the pressure of theperfusion solution in the first conduit. Since the pump stroke volume isconstant, a change in pressure will be indicative of a change in thevascular resistance of the organ.

The method further includes the step of adjusting the pump pulse rate inaccordance with the pressure of the perfusion solution in the firstconduit, which pressure is indicative of the organ's vascularresistance. The pulse rate of the pump will be decreased if the pressureof the perfusion solution in the first conduit increases, whichindicates that the vascular resistance of the organ has increased. Thepump pulse rate will be automatically increased if the pressure of theperfusion solution in the first conduit decreases, indicating that theorgan's vascular resistance has decreased.

Under normal physiologic conditions in the intact organism, activevasomotor control regulates tissue blood flow. In a state of hypothermia(such as is induced by cold perfusion), tissue denervation or tissueinjury, this vasomotor mechanism is diminished or lost. In addition,vascular wall permeability may be altered, further compromising exchangebetween the intravascular space and the tissues. Conventional organpreservation machines try to mimic normal physiological conditions andignore the particular requirements of hypothermic tissue. These machinesprovide too much flow at a high pulse rate which is damaging to thetissues. For proper hypothermic perfusion, the perfusion pressure shouldbe sufficient to open all vessels and perfuse the tissues. Sinceprotective vasomotor control is absent, a higher pressure than theminimal perfusion pressure can be damaging.

In the perfusion method of the present invention, this is accomplishedby the present high threshold. However, if this pressure weremaintained, then the continuous intravascular pressure would result inextravasation of fluids and result in edema. To minimize the possibilityof edema and allow for flow from the tissue back into the intravascularspace, the perfusion pressure is preferably pulsatile with a sufficientperiod of low pressure. The new perfusion method provides for a lowpressure phase by means of the preset low pressure threshold.

Hypothermic tissue is also much more rigid. This requires a much slowerpressure rise (dP/dT) than normal. The pressure rise dP/dT is optimalwhen the flow is in phase with the pressure. The rise in pressure can beadjusted independently from the high and low pressure thresholds bychanging the flow rate of the pump at the beginning of a new pulse. Thisallows for synchronization of phase of pressure and flow. To completethe perfusion for hypothermic tissue, the proper stroke volume ispreferably determined. The stroke volume is related to intravascularvolume which is not changed by hypothermia. Therefore, the stroke volumemay approximate the stroke volume under normothermic conditions for agiven tissue. In the perfusion apparatus of the present invention, thestroke volume is regulated by the size or capacitance of a compliancechamber preferably used in the apparatus, as will be described ingreater detail.

These and other objects, features and advantages of this invention willbe apparent from the following detailed description of illustrativeembodiments thereof, which is to be read in connection with theaccompanying drawings.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 is a pictorial illustration of one form of the apparatus of thepresent invention.

FIG. 2 is a block diagram of the pump control means illustrated by FIG.1.

FIG. 3 is a schematic diagram of a preferred form of the pump controlmeans illustrated by FIG. 2.

FIG. 4 is a pictorial illustration of a second form of the apparatus ofthe present invention.

FIG. 5 is a block diagram of the pump control means illustrated by FIG.4.

FIG. 6 is a schematic diagram of a preferred form of the pump controlmeans illustrated by FIG. 5.

DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

Referring initially to FIG. 1 of the drawings, it will be seen that anapparatus for perfusing a donor organ, constructed in accordance withthe present invention, includes an outer container 2 which, as will beseen, is adapted to hold the organ and the other elements and componentsof the perfusion system. The outer container 2 includes insulated walls4 formed of a highly insulative material, such as polystyrene or thelike. Outer container 2 is made watertight so that it may be at leastpartially filled with crushed ice 3, in the event that the system is tobe used for hypothermic organ perfusion.

Outer container 2 further includes an insulated top wall 14 which ispreferably closely received between container walls 4, and is positionedacross the upper portion of container 2. Thus, outer container 2 definesa leak-proof interior chamber 16 for receiving crushed ice. Insulatedtop wall 14 is removable so that container 2 may be filled with crushedice 3.

The outer container 2 further includes a cover or lid 6 which couplessnugly to the walls 4 of the container. The lid 6 includes a vent 5 or agas permeable membrane 7 to allow room air to oxygenate the perfusionsolution in the organ chamber, which will be described. However, lid 6is water impermeable to prevent perfusion solution from leaking fromcontainer 2.

A gas input/output port 8 is formed through the thickness of containerwall 4. Port 8 is adapted to receive a gas conduit 10 which, as will beseen, is adapted to be connected to a pump disposed internally of thecontainer 2, as well as being coupled to a gas source 12. Of course,conduit 10 is closely received in port 8 so as to prevent ice and waterfrom leaking from outer container 2.

The perfusion apparatus of the present invention further includes aninterior container 18 disposed completely or at least partially withinthe interior of container 2. Interior container 18 includes side walls20 and a bottom wall 22 connected to side walls 20. Side walls 20 andbottom wall 22 of container 18 thus define a chamber 24 for holding thedonor organ 26.

Interior container 18 is closely received by an opening 28 formed in topwall 14 of container 2. Accordingly, top wall 14 supports container 18so that container 18 extends into interior chamber 16 defined bycontainer 2. In its preferred form, the walls 20 and 22 of container 18are not insulated so that a organ 26 placed into chamber 24 will befurther cooled by the crushed ice contained in interior chamber 16 ofcontainer 2.

Interior container 18 further includes a removable cover 30 which snuglymates with side walls 20. Cover 30 preferably includes a gas permeablemembrane 32 which is provided so that the organ chamber 24 is exposed toroom air to maintain oxygenation of the perfusate. However, membrane 32is water impermeable so it will not leak. Cover 30 may further include avent orifice 34 formed through its thickness. Vent 34 is provided forremoving substantially all of the air from container 18.

Interior container 18 includes two openings 36, 38 which may be formedthrough side walls 20. As will be explained, each opening 36, 38 isformed to receive a conduit which provides perfusion solution to andremoves perfusion solution from chamber 24.

The organ perfusion system of the present invention further includes apump 40. Pump 40 generally includes a first container 42 which definesin its interior a perfusion solution drive chamber 44 and has mountedinteriorly an elastic diaphragm 46. Similarly, pump 40 includes a secondcontainer 48 which defines a compliance chamber 50 and an elasticdiaphragm 52 in its interior. Compliance chamber 50 is closed and, aswill be described, mimics the aorta by acting as a capacitor to storeenergy in the form of gas pressure. Part No. 2118-008, which is a 250ml. container manufactured by Nalgene Co., may be suitable for use aspump chambers 44, 50.

Pump 40, with its compliance chamber 50 and its drive chamber 44, isconnected to the donor organ 26 and the organ chamber 24 by first andsecond conduits 54, 56, respectively. More specifically, compliancechamber 50 is in communication with organ 26 through the first conduit54, with conduit 54 being connected to the main artery of organ 26,passing through opening 38 in interior container 18, with the other endof the conduit 54 being connected to a "T" fitting 58, whose second endis connected to second container 48.

Similarly, second conduit 56 is in communication with chamber 24 byhaving one of its ends pass through opening 36 in interior container 18.The other end of second conduit 56 is connected to a "T" fitting 60,whose second end is connected to first container 42.

In a preferred form of the invention, a one-way valve 62 may bepositioned in line with second conduit 56 between "T" fitting 60 andinterior container 18, with the valve situated such that it allows flowaway from the interior container 18 toward drive chamber 44. The thirdports of "T" fittings 58, 60 are connected together through a thirdconduit 64. In a preferred form, a one-way valve 66 may be positioned inline with third conduit 64, and situated such that flow of perfusionsolution will be restricted to a direction toward compliance chamber 50and away from drive chamber 44.

Pump 40 will cause perfusion solution to flow in the direction indicatedby arrows A in FIG. 1. That is, the perfusion solution will flow intothe main artery of the organ 26, and the venous effluent will becollected in interior container 18. The collected perfusion solution,after it has passed through organ 26, will be returned either by gravityor by a pump (not shown) through the second conduit 56 to drive chamber44.

As mentioned previously, pump 40 is connected to a source of gas throughconduit 10. More particularly, conduit 10 is connected to firstcontainer 42, defining drive chamber 44, and to a solenoid air valve 68.

Solenoid air valve 68 is positionable in two positions. In the firstposition of solenoid air valve 68, drive chamber 44 is in communicationwith gas source 12 through port A of solenoid air valve 68. In thesecond position of solenoid air valve 68, drive chamber 44 is incommunication with the atmosphere, so that gas pressure in the firstcontainer 42 defining drive chamber 44 may be vented through port B ofvalve 68.

A source of gas 12, such as carbon dioxide in a pressurized cylinder,may be connected to port A of solenoid air valve 68 through a fourthconduit 70. Alternatively, and in a preferred form of the invention, afirst gas regulator 72 is positioned in series with fourth conduit 70 tolower and regulate the air pressure from gas source 12. Preferably,first regulator 72 lowers the pressure in fourth conduit 70 to about 20psi. A suitable regulator for use as regulator 72 is Part No.R83-200-RNEA, manufactured by Norgren Co.

A second regulator 74 may also be connected in series with fourthconduit 70 and positioned between first regulator 72 and port A ofsolenoid air valve 68. Second regulator 74 lowers the pressure in fourthconduit 70 to 2 psi. Part No. R38-200-RNEA, manufactured by Norgren Co.,may be used for regulator 74. Accordingly, a gas pressure of 2 psi isprovided to drive chamber 44 whenever solenoid air valve 68 is in aposition to allow air flow through port A.

When solenoid air valve 68 is positioned to allow flow through port A,drive chamber 44 is pressurized, expelling solution from chamber 44 andcausing perfusion solution to flow through first conduit 54 into thedonor organ 26. This action also causes solution to flow into compliancechamber 50, compressing the gas on the other side of diaphragm 52.

When solenoid air valve 68 switches to allow air flow through port B,the pressurized gas in drive chamber 44 is vented to the atmosphere,causing perfusion solution collected in the bottom of interior chamber18 to flow through second conduit 56 back to pump 40, for recirculation.More specifically, solution returned to the pump 40 by conduit 56 willfill drive chamber 44, expelling the gas from the other side ofdiaphragm 46. The pressure of the compressed gas in compliance chamber48 will also force out the solution which has filled that chamber, whichsolution flows to organ 26. Compliance chamber 50 thus smoothes orintegrates the pumping action of pump 40, in much the same way as theaorta smoothes the pumping action of the heart, to provide a more evenflow.

The volume of the compliance chamber 48 is chosen so that it will at theminimum accommodate the stroke volume being used. Preferably, the volumeof the compliance chamber is 5 to 10 times the stroke volume.

To measure the pressure of the perfusion solution flowing into theartery of organ 26, which pressure is indicative of the vascularresistance of the organ to the perfusion solution, a pressure transducer76, as shown in FIGS. 2 and 3 of the drawings, is in communication withfirst conduit 54. More specifically, a fifth conduit 78 may be employedwhich is connected between pressure transducer 76 and a first port of a"T" fitting 80. The second and third ports of "T" fitting 80 areconnected in series with first conduit 54 between compliance chamber 50and organ 26. As will be explained, pressure transducer 76 is used tocontrol the activation of solenoid air valve 68, which will control thepulse rate at which pump 40 supplies perfusion solution to organ 26.

The pressurized gas cylinder, solenoid air valve 68, pressure regulators72, 74 and, as will be described, pump control circuit 82, may all bemounted on the outside wall or cover of container 2 while the pump andother components of the perfusion solution circuit are mounted insidecontainer 2. Thus, the ice in container 2 will keep the organ as well asthe perfusion solution cool, even if the solution is not circulating.

Referring now to FIG. 2 of the drawings, it will be seen that thehomeostatic organ preservation system of the present invention furtherincludes a pump control circuit 82.

Pump control circuit 82, which may be viewed as also including solenoidair valve 68, basically further includes a valve driver 84, a comparatorcircuit 86, a timer 88, a latching circuit 90, a low pressure thresholdcircuit 92 and a high pressure threshold circuit 94. An inverter 96 mayalso be included so that the timer 88 is activated on the inverse of thehigh threshold circuit's output signal. The operation of the pumpcontrol circuit 82 shown in FIG. 2 is described below.

Pressure transducer 76, which senses the pressure in first conduit 54and, indirectly, the vascular resistance of the organ 26, produces anoutput signal which varies in amplitude in accordance with the pressuresensed in first conduit 54. This output signal is provided on signalline 97 to high threshold circuit 94 and low threshold circuit 92. If,for instance, the pressure in first conduit 54 is very low, that is,below the thresholds set by low threshold circuit 92 and high thresholdcircuit 94, low threshold circuit 92 will produce an output signal whichis at a low logic level, and high threshold circuit 94 will produce anoutput signal which is at a high logic level. The output signals of lowthreshold circuit 92 and high threshold circuit 94 are providedrespectively on signal lines 98 and 100 to latching circuit 90.

The output signal of latching circuit 90 is provided to thenon-inverting input of comparator 86 on line 102. In response to the lowlogic level output signal from low threshold circuit 92 and the highlogic level output signal from high threshold circuit 94, latchingcircuit 90 will provide an output signal which is at a high logic levelto comparator 86.

High threshold circuit 94 also provides its output signal which, in theexample given above, is at a high logic level, to inverter 96 on line104. An output signal from inverter 96 is provided to the master reset(MR) input of timer 88 on line 106. Inverter 96 will thus invert thehigh logic level of the output signal of high threshold circuit 94 to alow logic level at the input of timer 88. Timer 88 is designed such thata positive logic level pulse on its input will cause timer 88 to resetinternally and to generate an output signal in the form of a positivegoing pulse, which output signal is provided on line 108 to theinverting input of comparator 86.

Accordingly, in the example provided above, the output of timer 88 is ata low logic level, as it normally is, which output signal is provided tothe inverting input of comparator 86 on line 108.

The output of comparator 86 is provided to the input of valve driver 84on line 110. The output signal of comparator 86 is at a high logic levelwhen the output of latching circuit 90 is at a high logic level and whenthe output signal of timer 88 is at a low logic level. A high logiclevel provided to the input of valve driver 84 on line 110 will turn onvalve driver 84. Valve driver 84 controls valve 68 and is connected tovalve 68 through line 112.

In the example given above, the output signal of pressure transducer 76is relatively low, that is, it is at a voltage level which is lower thanboth a predetermined threshold voltage level set for the high thresholdcircuit 94 and a predetermined voltage threshold level which is set forlow threshold circuit 92. As also explained previously, at such avoltage level from pressure transducer 76, valve driver 84 will turn onthe solenoid air valve 68, enabling the pump 40 to operate and pumpperfusion solution into organ 26.

As the pressure in first conduit 54 increases, pressure transducer 76will detect this increase in pressure, and its output signal willaccordingly increase in voltage. When the amplitude of the output signalof pressure transducer 76 rises above the predetermined thresholdvoltage level of low threshold circuit 92, the output of low thresholdcircuit 92 will change to a high logic level. However, the output signalon high threshold circuit 94 will remain at a high logic level, andlatching circuit 90 will remain in its present state, with a high logiclevel as its output signal.

When the pressure in first conduit 54 detected by transducer 76increases such that the amplitude of the output signal from transducer76 rises above the predetermined voltage set with respect to the highthreshold circuit 94, the output signal of the high threshold circuit 94will change from a high logic level to a low logic level, which willcause the output signal of latching circuit 90 to change from a highlogic level to a low logic level. The output signal of high thresholdcircuit 94 is also provided to inverter 96, and thus the signal providedto the input of timer 88 will change from a low logic level to a highlogic level, resetting timer 88. When timer 88 is reset, its outputsignal will go to a high logic level.

The low logic level provided to the non-inverting input of comparator 86by latching circuit 90 will cause the output signal of comparator 86 togo to a low logic level, causing valve driver 84 to turn solenoid valve68 off. This, in turn, will cause the pump to stop pumping perfusionsolution into the organ 26.

The pressure in first conduit 54 will decrease exponentially due to thevascular resistance of the organ and capacitance or storage effect ofcompliance chamber 50. The output signal from pressure transducer 76will decrease in amplitude to below the predetermined voltage thresholdlevel set with respect to high threshold circuit 94. The state of theoutput signal of high threshold circuit 94 will change from a low logiclevel to a high logic level. However, the output signal of latchingcircuit 90 will remain in its present low state.

The signal provided by inverter 96 to the input of timer 88 will now goto a low logic level. This will enable the timer to initiate apredetermined time delay. After the predetermined time delay haselapsed, the output of timer 88 will return to a low logic level.However, during the time that the output signal of timer 88 is at a highlogic level, the output signal of comparator 86 will be kept at a lowlogic level, and valve driver 84 will continue to keep valve 68 in anoff condition, disabling pump 40.

When the pressure of the perfusion solution in first conduit 54 drops toa level such that the output signal from transducer 76 falls inamplitude below the predetermined voltage threshold level of lowthreshold circuit 92, the output signal from threshold circuit 92 willchange to a low logic level. Latching circuit 90, which receives the lowlogic level output signal from low threshold circuit 92, and the highlogic level output signal from high threshold circuit 94, will changethe state of its output signal from a low to a high logic level on line102. If timer 88 has not timed out, that is, if the output signal oftimer 88 is still at a high logic level, the output signal fromcomparator 86 will remain at a low logic level (as will be explainedwith respect to the embodiment illustrated by FIG. 3, a pull-upresistor, which is not shown in FIG. 2, may be used to ensure that thehigh logic level on signal line 108 is at least slightly higher than thehigh logic level on line 102, to prevent comparator 86 from changing thestate of its output signal). Thus, valve driver 84 will continue todisable valve 68 and keep pump 40 in an off state.

However, when the output signal of timer 88 returns to a low logiclevel, comparator 86 will now provide a high logic level output signal.This will enable valve driver 84, which will turn valve 68 on and which,in turn, will cause pump 40 to start pumping perfusion solution to organ26 again. The cycle of pump control circuit 82 stated above then repeatsitself.

A chart illustrating the sequence of events in the cycle of the pumpcontrol circuit 82, as described previously, is shown below.

    __________________________________________________________________________    Pressure                                                                           Output                                                                              Line  Line Line                                                                              Line Line                                                                              Line                                       in Con-                                                                            Pressure                                                                            #98   #100 #106                                                                              #108 #102                                                                              #110                                                                              Valve                                  duit 54                                                                            Transducer                                                                          Low T.                                                                              High T.                                                                            M.R.                                                                              Timer                                                                              Q.sub.1                                                                           Driver                                                                            ON/       Description                  mm Hg                                                                              Volt  Logic Logic                                                                              Logic                                                                             Logic                                                                              Logic                                                                             Logic                                                                             OFF  Sequence                                                                           of Events                    __________________________________________________________________________    <8   <3    0     1    0   1    1   0   OFF  (1)  Power On, Pressure Low.                                                       Auto Reset Starts Time                                                        Delay.                       <8   <3    0     1    0   0    1   1   ON   (2)  Time Delay Completed                                                          Pump Pressurized by                                                           Valve Turn On.               ≧8                                                                          ≧3                                                                           1     1    0   0    1   1   ON   (3)  Lower Threshold                                                               Reached.                                                                      Pump Remains On.             8-30 3-9   1     1    0   0    1   1   ON   (4)  Flow Continues into                                                           Compliance Chamber and                                                        Organ, Pressure Rises.       ≧30                                                                         ≧9                                                                           1     0    1   1    0   0   OFF  (5)  Pressure Reached at                                                           Higher Threshold.                                                             Pump Turned Off.                                                              Timer Reset.                 ≦30                                                                         ≦9                                                                           1     1    0   1    0   0   OFF  (6)  Pressure Drops Again.                                                         Blow High Threshold                                                           Time Delay Started.          8-30 3-9   1     1    0   1    0   0   OFF  (7)  Compliance Chamber                                                            Continues to Empty.          ≦8                                                                          ≦3                                                                           0     1    0   1    1   0   OFF  (8)  Low Threshold Reached.                                                        Timer Didn't Time Out                                                         Yet.                         <8   <3    0     1    0   0    1   1   ON   (9)  Timer Timed Out.                                                              Cycle Restarts.              __________________________________________________________________________

The low pressure threshold is shown in the chart to be set at 3 volts,which corresponds to a pressure in conduit 54 of about 8 mm Hg. The highpressure threshold is also shown to be set at 9 volts, which correspondsto a pressure in conduit 54 of about 30 mm Hg. These are the preferredsettings for the low and high pressure thresholds. The high and lowpressure thresholds respectively correspond to the peak systolicpressure and the endiastolic pressure.

When the resistance to flow increases, more time will elapse before thepressure in conduit 54 declines to the lower pressure threshold. Thiswill prolong the pulse period and therefore decrease the pulse rate.Vice versa, when the resistance to flow decreases, less time will elapsebefore the pressure in conduit 54 declines to the lower pressurethreshold and the pulse rate will increase. The pulse rate can onlyincrease up to the point where the pulse period becomes as short as thepredetermined time delay.

The preset high pressure threshold protects the organ from too high apulse pressure. The time delay or minimal pulse period and the lowpressure threshold protect the organ from too much flow. This protectionis desired because even high flow at low pressure may damage the organ'smicrovasculature.

By presetting the perfusion pressure thresholds and minimal pulseperiod, the optimum perfusion parameters can be chosen for everydifferent temperature. By changing the size and/or pressure in thecompliance chamber, the stroke volume can be adjusted to accommodatedifferent sized organs.

The drawings of the pump chambers are schematic. In case a cell richperfusate is used (i.e., blood), the pump chambers and the valves aremade of highly bio-compatible materials, such as polyurethane and/orsilicone, while the contours and shape of the pump diaphragms andcontainers allow for non-turbulent flow and prevent stasis.

FIG. 3 shows a schematic diagram of a preferred form of the pump controlcircuit 82 shown in FIG. 2. The values of the components and partnumbers of the integrated circuits described herein and shown in FIG. 3are exemplary only and are understood not to limit the invention, asother values and components may be substituted for those shown by oneskilled in the art.

Pump control circuit 82 is preferably powered by a battery 114, so thatthe entire system can be portable. Of course, it is envisioned to bewithin the scope of the invention to have other sources of AC or DCvoltages power the unit. For purposes of illustration only, a 12-voltbattery 114 comprised of 8 1.5 volt AA batteries connected in series isused. Battery 114 is connected to an on-off switch 116, which can be asingle pole, single throw (SPST) switch. Switch 116 is then connected toa diode 118, whose anode is connected to the positive side of thebattery through the switch. The cathode of diode 118 is then connectedto the various components of the pump control circuit 82, the connectiongenerally being shown by using the designation VCC. Diode 118 is used toprotect the circuit in the event that the battery pack is inadvertentlyconnected to the circuit in reverse polarity.

Pressure transducer 76 is preferably Model No. 142-SC-01D, manufacturedby Sensym Manufacturing Corporation. Pressure transducer 76 produces anoutput signal which varies in voltage from approximately 0 volts toabout VCC, which is approximately 12 volts, if pressure transducer 76 ispowered by VCC. The output signal of pressure transducer 76 provided onthe "output" terminal of pressure transducer 76 is provided to theinverting input of comparator 120 through a 100K ohm resistor 122, andto the non-inverting input of comparator 124 through a 100K ohm resistor126. The non-inverting input of comparator 120 is connected to the wiperof a 20K ohm potentiometer 128, whose other terminals are connected toVCC and to ground. Similarly, the inverting input of comparator 124 isconnected to the wiper of a 20K ohm potentiometer 130, whose other twoterminals are connected to VCC and ground.

Comparator 120, and its associated resistors 122, 128, comprise the highthreshold circuit 94 shown in FIG. 2. Similarly, comparator 124, and itsassociated resistors 126, 130, comprise the low threshold circuit 92shown in FIG. 2. Potentiometer 128 is used to set the predetermined highthreshold level of comparator 120, and potentiometer 130 is used to setthe predetermined low threshold level of comparator 124.

Preferably, comparators 120, 124 comprise two comparators ofquad-comparator integrated circuit LM339 or the like. Because the LM339comparators have open collector outputs, a 47K ohm pull-up resistor 132is connected between VCC and the output of comparator 120, and a similar47K ohm resistor 134 is connected between VCC and the output ofcomparator 124.

The outputs of comparators 120 and 124 are respectively connected to theclear (CL) and preset (PRE) inputs of a D-type edge-triggered flip flop136. Flip flop 136 is one-half of a dual D-type edge-triggered flip flopCMOS integrated circuit, such as part number MC7474 manufactured byMotorola Semiconductor Incorporated. Flip flop 136 is represented inFIG. 2 by latching circuit 90. The "D" and clock (CL) inputs of flipflop 136 are grounded, and the "Q" output of flip flop 136 is providedto the non-inverting input of a third comparator 138, which comparatoris represented in FIG. 2 by comparator 86.

A fourth comparator 140 is used in the pump control circuit 82 shown inFIG. 3. The output of comparator 120 is provided not only to flip flop136, but also to the inverting input of comparator 140. A voltagedivider resistor network provides a predetermined voltage to thenon-inverting input of comparator 140. The voltage divider resistornetwork includes a 47K ohm resistor 142 connected from VCC to thenon-inverting input of comparator 140, and another 47K ohm resistor 144connected between the non-inverting input of 140 and ground. Comparator140 may be one of the comparators provided in the LM339 integratedcircuit described previously. If such is the case, then a 47K ohmpull-up resistor 146 may be employed and connected between VCC and theoutput of comparator 140.

Comparator 140 inverts the output signal from comparator 120 and, aswill be explained further, provides the inverted signal to the masterreset (MR) input of programmable timer 148. Comparator 140 isrepresented in FIG. 2 by inverter 96.

Programmable timer 148 is preferably a CMOS logic integrated circuit,Part No. MC14541B, manufactured by Motorola Semiconductor Incorporated.Programmable timer 148 is represented in FIG. 2 by timer 88.

Programmable timer 148 will produce an output signal in the form of ahigh logic level pulse having a duration which is set externally to theintegrated circuit by the selection of the values of certain capacitorsand resistors connected to timer 148. If the above-described Part No.MC14541B is used for programmable timer 148, it is seen from FIG. 3 thatpins 9, 12, 13 and 14 of the integrated circuit are connected to VCC,while pins 5, 7 and lo are grounded. Pin 2 and pin 3 of programmabletimer 148 are respectively connected to a 0.002 microfarad capacitor 150and a 390K ohm resistor 152, whose other ends are connected together andto one end of a 1 megohm potentiometer 154. Pin 1 of programmable timer148 is connected to one end of a 47K ohm resistor 156, whose other endis connected to the wiper of potentiometer 154. With the values ofresistors 152 and 156 and capacitor 150 described above, the duration ofa high level pulse provided on the output (pin 8) of programmable timer148 will nominally be about 20 seconds, with adjustment provided bypotentiometer 154. The output of timer 148 is provided to the invertinginput of comparator 138. Preferably, a 100K ohm resistor 158 isconnected to the output of timer 148 and to VCC to act as a pull-upresistor so that the signal from timer 148 is at least slightly higherthan the signal from flip flop 136. This is to ensure that the outputsignal of comparator 138 does not go to a high logic level when both ofits inputs are high.

As mentioned previously, comparator 138 is represented by comparator 86in FIG. 2. It may also be one of he four comparators provided inintegrated circuit Part No. LM339. If such is the case, a 47K ohmpull-up resistor 160 is provided and connected between VCC and theoutput of comparator 138.

Alternatively, comparator 86 may be replaced by a compatible 2-inputlogic gate which provides a high level output when the outputs of flipflop 136 and timer 148 (which are provided to the gate inputs) are highand low, respectively, and provides a low output at all other times.

The output of comparator 138 is connected to the gate of an N-channelMOSFET transistor 162 through a 10K ohm gate resistor 164. The source oftransistor 162 is connected to ground, while the drain of transistor 162is connected to VCC through diode 166. More specifically, the anode ofdiode 166 is connected to the drain of transistor 162, while the cathodeof diode 166 is connected to VCC. Diode 166 is provided for spikeprotection, as will be described.

Transistor 162 may be Part No. IRFD220 manufactured by InternationalRectifier Corp. in El Segundo, Calif. Transistor 162 is represented asthe valve driver 84 in FIG. 2.

The drain of transistor 162 is connected to one end of the solenoid orcoil of valve 68, and the other end of the solenoid is connected to VCC.When the solenoid de-energizes, diode 166 may conduct to VCC if anyover-voltage transients are produced, in order to protect transistor162. Solenoid air valve 68 is preferably a three-way air valve, Part No.3E1/12V, manufactured by Humphrey Manufacturing Company.

A light-emitting diode (LED) 168 is also provided. Light-emitting diodeis connected with its anode to VCC and its cathode to the drain oftransistor 162 through a 1K ohm resistor 170 LED 168 will conduct andlight whenever the solenoid is energized to turn pump 40 on.

The pump control circuit 82 shown schematically in FIG. 3 works in thesame manner as described with respect to the block diagram of thecircuit shown in FIG. 2. Potentiometer 130, which adjusts the lowpressure threshold level, is set to provide approximately 3 volts at theinverting input of comparator 124, which corresponds to a pressure of 8millimeters of mercury. Potentiometer 128, which adjusts the high levelpressure threshold, is set to provide 9 volts at non-inverting input ofcomparator 120, which corresponds to a pressure of about 30 millimetersof mercury.

Assuming initially that pressure transducer 76 produces an outputvoltage level which is below both the high and low threshold levels setby potentiometer 128 and 130, the outputs of comparators 120 and 124will be respectively at high and low logic levels. Accordingly, a lowlogic level is provided by comparator 124 to the preset of flip flop136, causing the "Q" output of flip flop 136 to go to a high logiclevel.

Timer 148 includes an auto-reset feature. Upon initial power turn on,the auto-reset of timer 148 will be activated and provide a logic highoutput for the duration of the predetermined time delay.

If the inverting input of comparator 138 is high, the output ofcomparator 138 will be at a logic low. After the timer has timed out,the inverting input of comparator 138 will go to a low logic level. Thiswill change the output of comparator 138 to a high logic level since thenon-inverting input remains high. This will bias transistor 162 so thatit is on and conducting current through the solenoid of valve 68. Theswitch contacts of valve 68 will be in the "A" position, as shown inFIG. 2, to allow gas from source 12 to flow into drive chamber 44 ofpump 40, causing perfusion solution to flow through first conduit 54into organ 26.

As the pressure in conduit 54 increases, pressure transducer 76 willdetect this increase and provide an output signal of greater voltage. Asthe output signal of transducer 76 increases, it will rise above the 3volt threshold level set by potentiometer 130, causing comparator 124 toswitch to a high logic level on its output. However, the high logiclevel provided to the preset of flip flop 136 will not affect the logiclevel on the "Q" output of the flip flop. Accordingly, pump 40 remainson.

As the pressure in first conduit 54 increases further, the outputvoltage of transducer 76 will reach the high threshold level set bypotentiometer 128, that is, 9 volts. At this point, comparator 120 willswitch from a high to a low logic level on its output. The low logiclevel is provided to the clear (CL) input of flip flop 136, causing the"Q" output of flip flop 136 to switch from a high logic level to a lowlogic level. This transition on the output of comparator 120 is invertedby comparator 140 so that the master reset input of programmable timer148 is provided with a high logic level. The transition from low to highwill reset timer 148, and the output of timer 148 will go to a highlogic level.

The low logic level provided on the non-inverting input of comparator138, or the high logic level provided by the timer 148 on the invertinginput of comparator 138, will cause the output of the comparator to goto a low logic level, cutting off transistor 162, i.e., so that it nolonger conducts current through the solenoid of valve 68. The associatedswitch of valve 68 will switch to the "B" position (see FIGS. 1 and 3)so that the gas in drive chamber 44 will be vented to the atmosphere.Pump 40 will stop circulating perfusion solution to the organ and thepressure in conduit 54 will drop.

As the pressure drops, the amplitude of the output signal of transducer76 will decrease below the value set for the high pressure threshold bypotentiometer 128. Such will cause the output of comparator 120 toreturn to a high logic level, but this will not affect the state of flipflop 136.

The master reset input of timer 148 will, however, go to a low logiclevel and, accordingly, the master reset input of timer 148 to a lowlogic level. This high-to-low transition on the master reset input oftimer 148 will trigger the timer. The output signal from timer 148 willremain at a high logic level for a predetermined duration, which isnominally set for 20 seconds from the time it is triggered. Thus,transistor 162 will remain in the cut-off condition, and solenoid valve68 will remain de-energized.

When the pressure in conduit 54 has decreased to such a point that theoutput voltage of transducer 76 has fallen below the lower threshold setby potentiometer 130, the output of comparator 124 will go to a lowlogic level, causing the "Q" output of flip flop 136 to change to a highlogic level. This will cause the output of comparator 138 to return to ahigh logic level, but only if programmable timer 148 has timed-out (thatis, only if the output signal on timer 148 has returned to a low logiclevel). When the output of comparator 138 returns to a high logic level,it will turn transistor 172 on so that current is conducted through thesolenoid of valve 68, switching the solenoid back to position "A" toallow gas to enter drive chamber 44, causing pump 40 to pump perfusionsolution into organ 26.

Note that every time transistor 162 is turned on to conduct currentthrough the solenoid of valve 68, current is also conducted through LED168, which lights to indicate that the pump 40 is pumping perfusionsolution into organ 26.

The above-described cycle will repeat itself periodically.

An alternative form of the homeostatic organ preservation system of thepresent invention is illustrated by FIGS. 4-6. The alternative form ofthe system is similar in structure, circuitry and function to the systemshown in FIGS. 1-3 and described previously, and like reference numeralsare used to indicate similar components.

Referring initially to FIG. 4 of the drawings, it will be seen that thealternative form of the organ preservation system comprises most of thebasic components of the first form shown in FIG. 1, and preferablyincludes the insulated outer container 2, the cover 6, interior organcontainer 18, perfusion flow conduits 54 and 56, and all of the othercomponents of the first system connected in the manner describedpreviously, except that one-way valves 62, 66, conduit 64, first pumpcontainer 42 defining drive chamber 44, fitting 60, and gas conduit 10are preferably omitted. In addition, the CO₂ gas source 12, regulators72, 74, conduit 70 and solenoid valve 68 are preferably eliminated fromthis embodiment of the system.

In accordance with the second form of the invention, the second orreturn conduit 56 passes through port 8 of container 4 and is coupled tothe input port of a separate pump 200, which may be mounted on theexterior surface of container 4. Pump 200 replaces, in effect, firstcontainer 42 defining drive chamber 44, and eliminates the need for asource of compressed gas.

Several types of pumps may be utilized as pump 200, many of which arecommercially available, as long as certain specifications are preferablymet. It is preferred if pump 200 has an adjustable flow rate, allows forintermittent operation to provide pulsatile flow, and is small enough tobe portable with the rest of the system. In addition, the pumppreferably should not contaminate the perfusate and should be safe forprotein and cell containing solutions. Possible pump types which may beused as pump 200 include a roller pump, a bellows or diaphragm operatedpump, an impeller pump, a piston pump, a pusher plate pump or any otherpump which preferably meets the above specifications. A suitable rollerpump 200 which may be used as pump 200 is Part No. SK10 manufactured bySarnes Inc. located in Ann Arbor, Mich.

The output port of pump 200 is connected to a conduit 202 which passesthrough a second port 204 formed through the thickness of insulatedcontainer 4. Conduit 202 is connected to fitting 58 so that roller pump200 is coupled to second container 48 defining the compliance chamber50. A pump control input terminal on pump 200 is connected to a pumpcontrol circuit 82', which is similar in many respects to pump controlcircuit 82 and which will be described in greater detail.

As in the previous embodiment, container 4 is made from a temperatureinsulating material. Hypothermia of the organ chamber 24 and perfusioncircuit is maintained by melting ice or other cooling means. The pumpcontrol circuit 82', the pump 200 and the power supply may be attachedto the outside of the container 4 or placed in a separate liquidproofchamber within container 4, if for example pump 200 is not submersiblein the cooling medium. Alternatively, pump 200 may be situated insidecontainer 4 in a manner similar to drive chamber container 42. Bymounting pump 200 inside the container, there is no need for conduits 56and 202 to pass through the container wall and be exposed to ambienttemperatures. Thus, the entire perfusion circuit will be exposed to thecooling medium inside the container 4.

The homeostatic organ preservation system illustrated by FIG. 4 operatesin a manner similar to that shown in FIG. 1. Pump 200 receives perfusionsolution returned to it from organ chamber 24, and pumps solutionthrough first conduit 54 into the donor organ 26. This action alsocauses solution to flow into compliance chamber 50, which is effectivelyplaced in series with pump 200 and the perfused organ, compressing thegas on the other side of diaphragm 52, as it did in the embodiment ofFIG. 1. The pressure of the compressed gas in compliance chamber 50 willalso force out the solution which has filled that chamber, whichsolution flows to organ 26. As mentioned previously in regard to theembodiment shown in FIG. 1, compliance chamber 50 of this alternativeembodiment smoothes or integrates the pumping action of the pump toprovide a more even flow. The capacity of the compliance chamber 50 isselected to provide a certain stroke volume. The capacity of thecompliance chamber and adjustments in the flow rate of the pump 200allow for the synchronization of the phase of the flow to the phase ofthe pressure.

The pump control circuit 82' is generally similar in structure andfunction to control circuit 82 of the first embodiment. As shown inblock diagram form in FIG. 5, pump control circuit 82' includes low andhigh pressure threshold circuits 92, 94, which effectively compare theperfusion pressure with preset low and high thresholds, pressuretransducer 76 which measures the perfusion pressure, latching circuit90, inverter 96, timer 88 which limits the maximum pulse rate, andcomparator 86, which is used for starting and stopping the action of thepump. Each of these components is included in the preferred form of theembodiment shown in FIG. 2, and all of these components in the secondform of the system are interconnected in the manner described previouslyin relation to the embodiment of FIG. 2.

The pump control circuit 82' includes a pump driver 84' coupled tocomparator 86 by line 110 and to pump 200 by line 206. Pump driver 84'functions in a manner similar to valve driver 84 described previously todrive pump 200 in response to the output signal comparator 86.

FIG. 6 shows a schematic diagram of a preferred form of the pump controlcircuit 82' shown in FIG. 5. The components of the pump control circuit82' are basically the same as those of circuit 82 shown in FIG. 3, andthese components are interconnected in the same manner describedpreviously, except that solenoid valve 68 is omitted, and the drain oftransistor 162 and one end of resistor 170 are coupled directly to thepump control input terminal (CTRL) of pump 200. In addition, a DCvoltage VCC is provided directly to the DC input of pump 200. Pumpcircuit 82' functions generally in the same manner in controlling pump200 as circuit 82 functions in controlling solenoid valve 68.

It is evident from the above description of the homeostatic organpreservation system that the system automatically responds to changes invascular resistance by altering the pulse rate of the pump while thesystolic perfusion pressure and the stroke volume remain constant. Thedifferential of pressure over time (dP/dt) may be adjusted independentlyfrom stroke volume and pulse pressure to match the decreased complianceof the hypothermic organ, or body if perfusion of the whole body isbeing performed. The appropriate settings of potentiometers 128, 130,which control the high and low pressure thresholds, and of potentiometer154, which controls the duration of timer 148, for a particular type oforgan can be precalibrated at the time of manufacturing the system,after which no further adjustments by the user are necessary. Also, ifthe system is to be used for normothermic perfusion, the normalphysiologic flow parameters may be set.

The timer circuit is advantageous in that it will prevent the pump fromoperating at too fast a rate. This will minimize any damage to theorgan's microvasculature which may result from a high flow rate ofperfusate even at a low pressure. In other words, the system of thepresent invention guarantees that peak pressure is provided to the organto perfuse all of its vessels, and provides a high flow rate but not adamaging flow. The 1 megohm potentiometer 154 will provide an adjustmentto the pump pulse rate of from about 6 beats per minute to about 0.5beats per minute. Potentiometer 154 is adjusted in accordance with thetemperature at which the organ is being perfused.

The entire perfusion system (i.e., the pump, organ chamber andinterconnecting conduits) is contained in one insulated container 2;therefore, the organ and the perfusate are maintained at a constanttemperature whether the pump is on or off. The constant temperaturemaintained in the system allows for exact redox control of theperfusate.

For a perfusion at different temperatures, it is envisioned that atemperature sensor (not shown) be employed which can automaticallycorrect the perfusion parameters (i.e., the high and low thresholdlevels and the timer duration) as required.

Also, it is envisioned to incorporate a perfusate filter 172 (seeFIG. 1) in the system, preferably in line with first conduit 54, havinga 0.2 micrometer pore size to prevent damage by cryoprecipitants or toclear the perfusate of cellular components. The advantage of the systemdescribed above is that the pump will automatically adjust to anypressure drop that might occur due to the filter. A 0.2 μm bypassfilter, Part No. PP3802 manufactured by Pall Corporation, is suitablefor use as filter 172.

All of the components of the system of the present invention are highlybiocompatible, and the perfusate is not exposed to high shear forcesduring perfusion. These features reduce the denaturization of proteinsand minimize the hemolysis of cells in the perfusate.

The internal power supply 114 is sufficient for several days ofindependent operation. This is also attributable to the low currentdrain resulting from the use of CMOS logic.

The entire unit is portable and weighs approximately six kilograms, and,in its preferred form, is relatively small with the dimensions of 38centimeters in height by 27 centimeters in width by 21 centimeters indepth. It is quite smaller and lighter than current machines which weighmore than 25 kilograms and are three times larger.

Also, the system of the present invention is quite inexpensive tomanufacture and use. The approximate cost of the materials are $125.00in reusable components and $50.00 in disposable materials. The simpleconstruction requires approximately three man-hours for assembly.

The method and apparatus of the present invention provide the optionalperfusion for tissues which have an altered or absent vasomotorregulation, as occurs during hypothermia, and is therefore ideal fororgan preservation for the purpose of transplantation. As is evidentfrom the previous description, the perfusion method of the presentinvention meets four basic design objectives: 1) the perfusion of theorgan is pulsatile wherein a new pulse starts substantially at the timethe pressure returns to a preset level; 2) the pulse pressures may bepreset and are substantially unaffected by changes in the vascularresistance of the tissue; 3) the stroke volume is substantially constantand substantially equals the stroke volume under normal physiologicalconditions for a given perfused organ; and 4) the phase of flow issubstantially synchronous with the phase of pressure. In addition, for agiven application, as for example human kidney preservation, theperfusion pressure threshold levels and the volume of the compliancechamber may be standardized.

The homeostatic organ preservation system of the present invention ismore adaptable than conventional perfusion devices to furtherimprovements. For example, filters, gas exchangers and redox controllersmay easily be placed in series with the apparatus of the presentinvention without substantially affecting perfusion characteristics.

Although illustrative embodiments of the present invention have beendescribed herein with reference to the accompanying drawings, it is tobe understood that the invention is not limited to those preciseembodiments, and that various other changes and modifications may beeffected therein by one skilled in the art without departing from thescope or spirit of the invention.

What is claimed is:
 1. A homeostatic organ preservation system, whichcomprises:means defining a chamber for holding a donor organ; a pump forproviding a perfusion solution to the organ, the pump being operable toprovide perfusion solution to the organ at a predetermined pump pulsepressure and a predetermined pump stroke volume; a first conduit coupledto the pump and adapted to be coupled to the organ, the first conduitbeing adapted to provide perfusion solution from the pump to the organ;a second conduit coupled to the pump and communicating with the organchamber, the second conduit being adapted to return perfusion solutionfrom the organ chamber to the pump; a pressure sensor coupled to thefirst conduit to sense the pressure of the perfusion solution in thefirst conduit and provided to the organ, the pressure sensor providingan output signal being indicative of the vascular resistance of theorgan; and pump control means for controlling the pump, the pump controlmeans being responsive to the output signal of the pressure sensor toraise and lower the pump pulse rate respectively in response to adecrease and increase in the organ vascular resistance.
 2. A system asdefined by claim 1, wherein the pump control means includes first andsecond pressure threshold comparators, the first pressure thresholdcomparator being responsive to the output signal of the pressure sensorand providing an output signal indicative of the relative amplitude ofthe output signal of the pressure sensor with respect to a firstpredetermined threshold value, the second pressure threshold comparatorbeing responsive to the output signal of the pressure sensor andproviding an output signal indicative of the relative amplitude of theoutput signal of the pressure sensor with respect to a secondpredetermined pressure value.
 3. A system as defined by claim 2, whereinthe pump control means further includes latching means, the latchingmeans being responsive to the output signals of the first and secondpressure threshold comparators and providing an output signal inresponse thereto.
 4. A system as defined by claim 3, wherein the pumpcontrol means further includes timer means, the timer means beingresponsive to the output signal of the second pressure thresholdcomparator and providing an output signal in the form of a pulse of apredetermined duration.
 5. A system as defined by claim 4, wherein thepump control means further includes a third comparator, the thirdcomparator being responsive to the output signal of the latching meansand the output signal of the timer means and providing an output signalin response thereto.
 6. A system as defined by claim 5, wherein the pumpcontrol means further includes valve driver means, the valve drivermeans being responsive to the output signal of the third comparator andproviding an output signal in response thereto.
 7. A system as definedby claim 6, wherein the pump control means further includes a gas valve,the gas valve being responsive to the output signal of the valve drivermeans to selectively provide pressurized gas to the pump in responsethereto.
 8. A system as defined by claim 5, wherein the pump controlmeans further includes pump driver means, the pump driver means beingresponsive to the output signal of the third comparator and providing anoutput signal in response thereto, the pump being responsive to theoutput signal of the pump driver means to provide perfusion solution tothe organ.
 9. A homeostatic organ preservation system, whichcomprises:an outer container, the outer container having side wallsformed of a thermally insulating material, the outer container beingsubstantially liquid-tight and defining a first chamber in the interiorthereof; an inner container, the inner container being at leastpartially disposed within the first chamber of the outer container, theinner container defining a second chamber for receiving an organ; acover removably mounted on at least one of the inner container and theouter container, the cover including means for allowing air to passtherethrough; a pump for providing a perfusion solution to an organdisposed in the second chamber, the pump being disposed within the firstchamber of the outer container; at least a first and second conduit forrespectively supplying perfusion solution to the organ and removingsolution from the second chamber, the first and second conduits beingdisposed in the first chamber, the first conduit providing communicationbetween the organ and the pump, and the second conduit providingcommunication between the second chamber and the pump; a pressure sensorcoupled to the first conduit to sense the pressure of the perfusionsolution in the first conduit and provided to the organ, the pressuresensor providing an output signal being indicative of the vascularresistance of the organ; and pump control means for controlling thepump, the pump control means being responsive to the output signal ofthe pressure sensor to raise and lower the pump pulse rate respectivelyin response to a decrease and increase in the organ vascular resistance;wherein the pump, first and second conduits and second chamber define acircuit for recirculating perfusion solution between the organ and thepump, the circuit being contained within the first chamber.
 10. A systemas defined by claim 9, wherein the pump includes means defining a pumpchamber and means defining a compliance chamber, the pump chamber andcompliance chamber being in communication with one another and with theperfusion solution circuit defined by the first and second conduits andthe second chamber.
 11. A system as defined by claim 10, wherein thesecond conduit is connected between the second chamber and the pumpchamber, and the first conduit is connected to the compliance chamberand is in communication with the organ.
 12. A system as defined by claim11, which further includes a first one-way valve coupled to the secondconduit to allow flow of perfusion solution in a direction only from thesecond chamber to the pump chamber, and a second one-way valveoperatively disposed between the pump chamber and the compliance chamberto allow flow of perfusion solution in a direction only from the pumpchamber to the compliance chamber.
 13. A system as defined by claim 9,which further includes a filter disposed in series communication withthe perfusion solution circuit defined by the pump, first and secondconduits and the second chamber.
 14. A homeostatic organ preservationsystem, which comprises:means defining a chamber for holding a donororgan; a pump for providing a perfusion solution to the organ, the pumpbeing operable to provide perfusion solution to the organ at apredetermined pump pulse pressure and a predetermined pump strokevolume; a first conduit coupled to the pump and adapted to be coupled tothe organ, the first conduit being adapted to provide perfusion solutionfrom the pump to the organ; a second conduit coupled to the pump andcommunicating with the organ chamber, the second conduit being adaptedto return perfusion solution from the organ chamber to the pump; apressure sensor coupled to the first conduit to sense the pressure ofthe perfusion solution in the first conduit and provided to the organ,the pressure sensor providing an output signal being indicative of thevascular resistance of the organ; a pump control circuit, the pumpcontrol circuit including: a first comparator, the first comparatorbeing provided with a low pressure threshold voltage and beingresponsive to the output signal of the pressure sensor, the firstcomparator providing an output signal indicative of the relativeamplitude of the output signal of the pressure sensor with respect tothe low pressure threshold voltage; a second comparator, the secondcomparator being provided with a high pressure threshold voltage andbeing responsive to the output signal of the pressure sensor, the secondcomparator providing an output signal indicative of the relativeamplitude of the output signal of the pressure sensor with respect tothe high pressure threshold voltage; a latching circuit, the latchingcircuit being responsive to the output signals of the first and secondcomparators and providing an output signal in response thereto; a timer,the timer being responsive to the output signal of the second comparatorand being triggered thereby when the amplitude of the output signal ofthe pressure sensor decreases from above to below the high pressurethreshold voltage, the timer providing an output signal in the form of apulse of a predetermined duration; means responsive to the outputsignals of the latching circuit and the timer and providing an outputsignal in response thereto; valve driver means, the valve driver meansbeing responsive to the output signal of the timer an latching circuitresponsive means and providing an output signal in response thereto; anda gas valve, the gas valve being responsive to the output signal of thevalve driver means to selectively provide pressurized gas to the pump inresponse thereto.
 15. A homeostatic organ preservation system, whichcomprises:means defining a chamber for holding a donor organ; a pump forproviding a perfusion solution to the organ, the pump being operable toprovide perfusion solution to the organ at a predetermined pump pulsepressure and a predetermined pump stroke volume; a first conduit coupledto the pump and adapted to be coupled to the organ, the first conduitbeing adapted to provide perfusion solution from the pump to the organ;a second conduit coupled to the pump and communicating with the organchamber, the second circuit being adapted to return perfusion solutionfrom the organ chamber to the pump; a pressure sensor coupled to thefirst conduit to sense the pressure of the perfusion solution in thefirst conduit and provided to the organ, the pressure sensor providingan output signal being indicative of the vascular resistance of theorgan; a pump control circuit, the pump control circuit including: afirst comparator, the first comparator being provided with a lowpressure threshold voltage and being responsive to the output signal ofthe pressure sensor, the first comparator providing an output signalindicative of the relative amplitude of the output signal of thepressure sensor with respect to the low pressure threshold voltage; asecond comparator, the second comparator being provided with a highpressure threshold voltage and being responsive to the output signal ofthe pressure sensor, the second comparator providing an output signalindicative of the relative amplitude of the output signal of thepressure sensor with respect to the high pressure threshold voltage; alatching circuit, the latching circuit being responsive to the outputsignals of the first and second comparators and providing an outputsignal in response thereto; a timer, the timer being responsive to theoutput signal of the second comparator and being triggered thereby whenthe amplitude of the output signal of the pressure sensor decreases fromabove to below the high pressure threshold voltage, the timer providingan output signal in the form of a pulse of a predetermined duration;means responsive to the output signals of the latching circuit and thetimer and providing an output signal in response thereto; and pumpdriver means, the pump driver means being responsive to the outputsignal of the timer and latching circuit responsive means and providingan output signal in response thereto, the pump being responsive to theoutput signal of the pump driver means to provide perfusion solution tothe organ.
 16. A method of perfusing an organ, the organ being placed ina chamber and connected to a first conduit which is connected to a pump,the chamber being in communication with the pump through a secondconduit, the pump providing a perfusion solution to the organ throughthe first conduit and the solution being returned to the pump throughthe second conduit, the pump being operable to provide perfusionsolution to the organ at a predetermined pump pulse pressure andpredetermined pump stroke volume, the method comprising the stepsof:monitoring the pressure of the perfusion solution in the firstconduit, the pressure being indicative of the vascular resistance of theorgan being perfused; and adjusting the pump pulse rate in accordancewith the pressure of the perfusion solution in the first conduit, thepulse rate of the pump being decreased if the pressure of the perfusionsolution in the first conduit increases, and being increased if thepressure of the perfusion solution in the first conduit decreases.
 17. Amethod of perfusing an organ, the organ being placed in a chamber andconnected to a first conduit which is connected to a pump, the chamberbeing in communication with the pump through a second conduit, the pumpproviding a perfusion solution to the organ through the first conduitand the solution being returned to the pump through the second conduit,the method comprising the steps of:monitoring the pressure of theperfusion solution in the first conduit, the pressure being indicativeof the vascular resistance of the organ being perfused; comparing a lowpressure threshold with the monitored pressure of the perfusion solutionand providing a first signal indicative of the relative magnitude of themonitored pressure with respect to the low pressure threshold; comparinga high pressure threshold with the monitored pressure of the perfusionsolution and providing a second signal indicative of the relativemagnitude of the monitored pressure of the perfusion solution withrespect to the high pressure threshold; providing a latched third signalin response to the first and second signals; energizing the pump inresponse to the third latched signal; and disabling the pump for apredetermined time interval following the monitored pressure decreasingin magnitude from above to below the high pressure threshold.
 18. Asystem as defined by claim 1, wherein the pump control means isresponsive to the output signal of the pressure sensor to raise andlower the pump pulse pressure respectively in response to a decrease andincrease in the organ vascular resistance.
 19. A system as defined byclaim 9, wherein the pump control means is responsive to the outputsignal of the pressure sensor to raise and lower the pump pulse pressurerespectively in response to a decrease and increase in the organvascular resistance.
 20. A method as defined by claim 16, which furtherincludes adjusting the pump pulse pressure in accordance with thepressure of the perfusion solution in the first conduit, the pulsepressure being decreased if the pressure of the perfusion solution inthe first conduit increases, and being increased if the pressure of theperfusion solution in the first conduit decreases.